The objective of this proposal is to examine the changes in airway smooth muscle sensitivity and responsiveness which occur during ontogenesis. Our methods will include an in vivo determination of airway sensitivity in guinea pigs during ontogenesis. We will perform longitudinal and cross-sectional studies of airway sensitivity with special emphasis on occurrence, development and duration of airway hyperreactivity/ hypersensitivity in vivo during ontogenesis. Tracheal, bronchial, and parenchymal preparations will be removed from animals of known age and sex and the sensitivity and responsiveness of these isolated tissues to contractile and relaxant agonists will be assessed. Sensitivity will be determined from concentration effect curves and responsiveness will be determined from maximally induced tensions normalized using wet weight, dry weight, adenosine diphosphate or creatine as a measure of muscle mass. Preliminary data suggest that changes in contraction/relaxation of airway muscle during development may be related to (a) changes in drug receptor densities and/or affinities and (b) the role of calcium. To examine these hypotheses, we will first measure the ontogenic changes to various agonists in vivo and correlate these changes with pharmacological and receptor measurements using isolated airway muscle and membrane preparations. Receptor properties will be assessed using standard radioligand binding assays with (125I) iodehydroxybenzyl pindolol. We will study the role of calcium in the ontogenic process by examining contractile and relaxant drugs under conditions where calcium concentration or flux is altered. Calcium transport will be changed using agents affecting calcium transport e.g. local anesthetics, verapamil. We believe the results will extend models of airway smooth muscle function. Such knowledge will aid in the elucidation of the pathogensis of disease conditions associated with airway hyperractivity, espically childhood asthma.